ML39356 Emicizumab Expanded Access Program

Principal Investigator: Hassan Yaish
Keywords: Hemophilia , Emicizubab , Inhibitors Department: Pediatric Administration
IRB Number: 00101085 Co Investigator:  
Specialty: Pediatric Hematology and Oncology
Sub Specialties: Hemophilia
Recruitment Status: Recruiting

Contact Information

Rebbecca Hanshew

Brief Summary

Objectives and Assessments

The objective of this Expanded Access Program (EAP) is to provide access to emicizumab to eligible patients with hemophilia A with factor VIII (FVIII) inhibitors before it is commercially available in the United States for the indication of hemophilia A with FVIII inhibitors. Discontinuation may occur earlier if patient or physician decides to discontinue treatment or the Sponsor discontinues emicizumab clinical development.
This EAP will also collect safety data. Safety parameters include incidence and severity of adverse events graded according to the World Health Organization (WHO) toxicity grading scale. In addition, patients will be followed at periodic clinic visits during the study.

Study Design

Description of Study
This is an open-label, multicenter EAP designed to provide emicizumab to patients (adults and adolescents ≥ 12 years old) with hemophilia A with FVIII inhibitors.
Enrollment will be based on eligibility, date of screening, and emicizumab availability.

Enrollment to the EAP will end on the day that emicizumab becomes commercially available in the United States following approval by the Food and Drug Administration (FDA) for the indication of hemophilia A with FVIII inhibitors. Treatment with emicizumab in this EAP may continue to be provided to those patients already enrolled in the EAP until the patient is able to obtain commercial drug or the patient withdraws from the EAP.
Screening will occur over a 4-week period. This EAP will include patients aged ≥ 12 years with hemophilia A who have inhibitors against FVIII and continue to have bleeds of any severity, despite treatment with current FDA-approved therapies. Patients who fail to meet eligibility criteria may be rescreened up to two times.

After screening, patients who meet the eligibility criteria may begin treatment with emicizumab at a loading dose of 3 mg/kg/week SC for 4 weeks, followed by a maintenance dose of 1.5 mg/kg/week SC thereafter. Patients who are currently receiving prophylactic therapy will discontinue their current prophylactic therapy before initiating treatment with emicizumab in the EAP. A washout period of 72 hours prior to the first emicizumab dose in this study is required for patients receiving prior aPCC or ITI.

Patients may require treatment of potential breakthrough bleeds, especially for the time period until steady-state concentrations of emicizumab have been reached. In the ongoing Phase IIIStudy BH29884 (adolescent and adult patients with hemophilia A with FVIII inhibitors), two events of TMA and two thromboembolic events were observed in patients who concomitantly used repeated doses of aPCC for the treatment of breakthrough bleeds. Therefore, it is recommended that breakthrough bleeds are treated with rFVIIa only, if possible, and that the use of aPCC or other bypassing agents should be avoided or limited. For patients who experience a breakthrough bleed that requires treatment with bypassing agents, local and central laboratory assessments are required to monitor the risk for thromboembolic events or TMA as per the schedule of assessments.

Treatment with emicizumab will continue until unacceptable toxicity, withdrawal of consent, patient or physician decision to discontinue treatment, death, the patient is able to obtain commercial drug after emicizumab becomes commercially available in the United States following approval of emicizumab for the indication of hemophilia A with FVIII inhibitors by the FDA, or the Sponsor decides to discontinue emicizumab clinical development, whichever occurs first.

All patients will be monitored for safety during treatment with emicizumab and for up to 24 weeks after the last dose of emicizumab as provided through this EAP or until initiation of therapy with commercial emicizumab.



Inclusion Criteria

Inclusion Criteria
Patients must meet the following criteria for study entry:

• Signed Informed Consent Form and assent form (if applicable)

– For patients below the legal age of consent, the parent(s)/legally authorized representative must be willing to give written informed consent, and

– The child may be required to give written informed assent (if able, and required by local laws or Institutional Review Board [IRB])

• Age ≥ 12 years

• Able to comply with the study protocol, in the investigator’s judgment

– For patients below the legal age of consent, both child and parent must be able comply with study requirements.

• Body weight ≥ 40 kg at the time of screening

• Diagnosis of congenital hemophilia A of any severity and documented history of high-titer inhibitor (i.e., ≥ 5 Bethesda Units)

• History of treatment with episodic or prophylactic bypassing agents for at least the last 24 weeks

• ≥ 6 (if on an episodic bypassing agent regimen) or ≥ 2 (if on a prophylactic bypassing agent regimen) bleeds within 24 weeks prior to screening

• Currently using rFVIIa or are willing to switch to rFVIIa as primary bypassing agent for the treatment of breakthrough bleeds

• Adequate hematologic function, defined as platelet count ≥ 100,000/μL and hemoglobin ≥ 8 g/dL (4.97 mmol/L) at screening

• Adequate hepatic function, defined as all the following at screening:
– Total bilirubin ≤ 1.5 × the upper limit of normal (ULN) (excluding Gilbert’s syndrome)
– Both AST and ALT ≤ 3 × ULN
– No clinical signs or known laboratory/radiographic evidence consistent with cirrhosis

• Adequate renal function, defined as serum creatinine ≤ 2.5 × ULN and creatinine clearance by Cockcroft-Gault formula ≥ 30 mL/min

• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 24 weeks after the last dose of emicizumab

– A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus).

– Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, established, proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. Alternatively, two methods (e.g., two barrier methods such as a condom and a cervical cap) may be combined to achieve a failure rate of < 1% per year. Barrier methods must always be supplemented with the use of a non-lipid-based spermicide.

– The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.

Exclusion Criteria

Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

• Inherited or acquired bleeding disorder other than hemophilia A

• Ongoing (or plan to receive during the study) immune tolerance induction therapy or prophylaxis with FVIII with the exception of patients who have received a treatment regimen of FVIII prophylaxis with concurrent bypassing agent prophylaxis

– For patients who have received prior aPCC or ITI, a washout period of 72 hours is required prior to the first emicizumab dose.

• History of illicit drug or alcohol abuse within 48 weeks prior to screening, in the investigator’s judgment

• Treatment for thromboembolic disease within 12 months before Day 1 (with the exception of previous catheter-associated thrombosis for which antithrombotic treatment is not currently ongoing) or current signs of thromboembolic disease

• Other conditions (e.g., certain autoimmune diseases) that may increase the risk of bleeding or thrombosis

• High risk for thrombotic microangiopathy (TMA; e.g., have a previous medical or family history of TMA), in the investigator’s judgment

• History of clinically significant hypersensitivity associated with monoclonal antibody therapies or components of the emicizumab injection

• Known HIV infection with CD4 count < 200 cells/μL within 24 weeks prior to screening

• Use of systemic immunomodulators (e.g., interferon or rituximab) at enrollment or planned use during the study, with the exception of antiretroviral therapy

• Treatment with any of the following:

– An investigational drug to treat or reduce the risk of hemophilic bleeds within 5 half-lives of last drug administration before Day 1

– A non-hemophilia-related investigational drug within the last 30 days or 5 half-lives before Day 1, whichever is longer

– An investigational drug concurrently

• Planned surgery (excluding minor procedures such as tooth extraction or incision and drainage) during the study

• Any serious medical condition, treatment, or abnormality in clinical laboratory tests that, in the investigator’s judgment, precludes the patient’s safe participation in the study

• Pregnant or lactating, or intending to become pregnant during the study

– Women of childbearing potential must have a negative serum pregnancy test result within 7 days before Day 1.